Schizophrenia is a complex disorder with a heritability of around 80%. Identifying disease-related genetic factors has been a major focus of schizophrenia research in recent years. Efforts have been multifaceted with the ultimate goal being to describe a causal path from specific genetic variants, to CNS protein changes, to changes in neuronal functioning, to behavioral effects associated with specific functional impairments. Past efforts to elucidate this causal path have been frustrated by the apparent heterogeneity of the syndrome, which may explain repeated failures to replicate identified disease loci. The schizophrenia diagnosis likely reflects a heterogeneous combination of several such causal paths, and is therefore characterized by a varying collection of phenotypes each associated with specific neurocognitive deficits reflecting the effects of a small subset of genes (or single gene) which act in conjunction with epigenetic processes and environmental factors. Traditional genetic approaches that focus on the presence or absence of the syndromal clinical phenotype, or its symptom domains have generally been less informative than approaches that focus more on disease-related phenotypes. In light of these complexities there is a critical need for alternative phenotypes that reflect specific aspects of disease risk. The catechol-O-methyl transferase (COMT) gene has been implicated in the pathophysiology of schizophrenia by its unique effect on prefrontal dopamine transmission. Frontal cortical neurons play an important role in the modulation of predictive SPEM. Our laboratory has refined several neurophysiological measures that reflect more specific aspects of neuronal functioning (e.g., the development and validation of predictive pursuit gain [PPG] of SPEM). We have applied PPG in an association study with COMT genotype with preliminary data showing a COMT by diagnosis interaction. We selected SPEM because it is an accepted schizophrenia endophenotype with a similar construct to working memory (WM). Our preliminary data suggests a paradoxical effect of COMT genotype on PPG in schizophrenia but not in normal subjects. In the current application, we aim to replicate our SPEM/COMT findings in a larger sample. We will also test the hypothesis that Met/Met COMT, and T/T DAT1 genotypes will result in decreased PPG performance in schizophrenia. In an exploratory framework, we will examine variations in other candidate dopamine genes, the dopamine 2 receptor (DRD2) and the dopamine .3 receptor (DRD3) genes. We will examine the effects of these genes on executive cognition (WCST), WM using Wechsler Adult Intelligence Scale Letter-Number-Sequencing subtest (WAIS-III L-N-S), and visuospatial WM (memory guided saccade). Deciphering the genetic mechanisms of prefrontal dopamine dysfunction in schizophrenia would advance our understanding of the pathophysiology of schizophrenia and may help identify novel treatments. [unreadable] [unreadable] [unreadable]